2024-02-11 23:03:05
12.02.2024
A computer program allows researchers to design artificial DNA sections that display cell states in real time. As Gaetano Gargiulo’s team writes in “Nature Communications”, the tool can improve drug screening once morest cancer and viral infections as well as immunotherapies.
All cells in our body rely on the same genetic material – and yet they each have different identities, functions and disease states. Being able to easily distinguish between the respective cells in real time would be extremely useful for many scientists who want to understand, for example, inflammatory processes, infections or cancer.
A team at the Max Delbrück Center has now created an algorithm that takes over the design of the appropriate tool. At the heart of the tool are stretches of DNA called sLCRs (“synthetic locus control regions”), which indicate the identity and state of cells. The technology can be used in various biological systems, reports a team led by Dr. Gaetano Gargiulo now in “Nature Communications”.
“Thanks to the algorithm, we can create precise DNA tools to mark and examine cells. They provide new insights into the behavior of the cells,” says Gargiulo, head of the “Molecular Oncology” working group and last author of the study. “We hope this will allow us to understand and manipulate cells more directly and in a more scalable way.”
It all started with Dr. Carlos Company, at the time a PhD student in the working group and one of the first authors, wanted to automate the adaptation of the DNA tools and thus make them accessible to other researchers. He programmed an algorithm. This can generate appropriate instruments for analyzing fundamental cellular processes, but also disease processes such as cancer, inflammation and infections.
“With this tool, researchers can study how a cell changes and takes on a different identity. All the important information that controls this change is summarized in simple synthetic DNA sequences. This makes it particularly innovative and makes it possible to study complex cellular behavior fields such as cancer or during development,” says Company.
The algorithm creates a tailor-made DNA tool
The computer program is called LSD – short for “logical design of synthetic cis-regulatory DNA”. The researchers enter genes and transcription factors that they know are related to the cell state in question. The program then identifies DNA segments (promoters and transcription amplifiers) that control the state of each cell. Nothing more is necessary – the researchers do not yet need to know the exact genetic or molecular mechanism that determines the cell’s behavior.
In the genomes of mice or humans, the program looks for those places where the transcription factors are most likely to dock, says Yuliia Dramaretska, also a doctoral student in Gargiulo’s laboratory and first author of the study. It then spits out a list of relevant sequences, each 150 base pairs long, that might be promoters or enhancers in a disease. “Of course this is not a random list,” she says. “The algorithm sorts them according to relevance and finds the sections that best represent the respective phenotype.”
Like a lamp in the cells
The scientists can then use these sections to build a tool called sLCR: It consists of the best-matching sequence and a section of DNA that encodes a fluorescent protein. “You can think of the sLCRs as an automated lamp that you build into the cell. It only turns on when the cell reaches the state you are interested in,” says Dr. Michela Serresi, scientist in Gargiulo’s working group and also first author of the study. The luminous color of the “lamp” may vary depending on the condition. Scientists can use fluorescence microscopy to observe the cells and immediately assign their condition based on the color. “We can see the color change with the naked eye in the Petri dish when we add active ingredients,” says Serresi.
The team tested the use of the computer program, for example, to test active ingredients on cells infected with SARS-CoV-2. They published the results in “Science Advances”. They have also used it to look for the disease mechanisms behind particularly dangerous brain tumors – glioblastomas – which individual drugs cannot cure. “In order to find effective therapy combinations that target specific cell conditions in glioblastomas, you not only have to know what defines these conditions. You have to see them as soon as they arise,” says Dr. Matthias Jürgen Schmitt, scientist in Gargiulo’s laboratory and first author. He applied the concept in the laboratory.
Another example: immune cells that have been modified in the laboratory so that they can recognize a specific cancer and kill the tumor cells. When a patient receives an infusion with these immune cells, not all of the cells work as hoped. While some are very effective, others are quickly exhausted. With the help of an ERC grant, Gargiulo’s group wants to use their tools to improve the production of this sensitive cell-based cancer therapy. “With the right collaborations, the tool can enable advances in many areas – whether it’s cancer, viral infections or immunotherapies,” says Gargiulo.
Those: Max Delbrück Center for Molecular Medicine (MDC)
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